TY - JOUR
T1 - SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness
AU - Carrozzo, Rosalba
AU - Dionisi-Vici, Carlo
AU - Steuerwald, Ulrike
AU - Lucioli, Simona
AU - Deodato, Federica
AU - Di Giandomenico, Sivia
AU - Bertini, Enrico
AU - Franke, Barbara
AU - Kluijtmans, Leo A.J.
AU - Meschini, Maria Chiara
AU - Rizzo, Cristiano
AU - Piemonte, Fiorella
AU - Rodenburg, Richard
AU - Santer, René
AU - Santorelli, Filippo M.
AU - Van Rooij, Arno
AU - Vermunt-De Koning, Diana
AU - Morava, Eva
AU - Wevers, Ron A.
N1 - Funding Information:
The authors thank the relatives of the Faroese patients for their willingness to give blood for the genome scan and the Faroese health authorities for allowing us to investigate a large cohort from these families at the molecular genetic level. Furthermore we thank R. Baumgartner and S. Yano who referred their patients to us, David O. Lambeth for the kind gift of the SUCLA2 antibody and C. Augustin for the DNA fingerprint analysis. Also we thank Dr S. J. R. Heales (Institute of Neurology, London, UK) for providing the data on the respiratory chain complexes of patient 13 in this article. The financial support of the Italian Ministry of Health (Ricerca Corrente e Finalizzata) and the Clinical Genetics Centre Nijmegen, The Netherlands is gratefully acknowledged.
PY - 2007/3
Y1 - 2007/3
N2 - One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G → A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1:2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.
AB - One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G → A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1:2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.
KW - Methylmalonic aciduria
KW - Succinyl-CoA synthetase
KW - Succinylcarnitine
KW - TCA cycle defect
KW - mtDNA depletion
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U2 - 10.1093/brain/awl389
DO - 10.1093/brain/awl389
M3 - Article
C2 - 17301081
AN - SCOPUS:33947165311
SN - 0006-8950
VL - 130
SP - 862
EP - 874
JO - Brain
JF - Brain
IS - 3
ER -